Hand-foot syndrome
BMJ published the results of a multi-center randomized and placebo-controlled double-blind phase 3 trial evaluating the efficacy of oral methylcobalamin (vitamin B12) to help prevent hand-foot syndrome among women receiving capecitabine treatment for human epidermal growth factor receptor 2 (HER2) negative early breast cancer. A range of 29–73% of women receiving treatment with capecitabine experience hand-foot syndrome, characterized by redness, pain, swelling, and dysesthesia in the palms and soles, which can progress to blistering, ulceration, etc., often limiting the effective dose. Methylcobalamin has shown some promise with neuropathy from other causes, including type 1 diabetes as well as type 2 diabetes (combined with dapagliflozin), prompting this larger controlled trial.
Two-hundred thirty-four women (median age 50 years) were randomized to receive either 500 mcg oral methycobalamin, taken three times per day, or a placebo for a maximum of 24 weeks. All women were taking oral capecitabine 2000 mg/m2/day in divided doses and in 21-day cycles. The primary endpoint of the study was the incidence of the first occurrence of grade ≥2 hand-foot syndrome, with a number of secondary endpoints, including overall survival, rates of discontinuation of capecitabine, etc.
Women taking methylcobalamin were found to have a significantly lower risk of hand-foot syndrome (the primary endpoint), occurring in 14.5% as compared to 29.1% with placebo. This benefit was observed among all patient subgroups, and in both the intention-to-treat and per-protocol analyses. Regarding secondary endpoints, a lower proportion of women reduced or discontinued treatment while taking methylcobalamin vs. placebo, but this difference was not significant. No significant survival differences were observed, or differences in the time to onset of hand-food syndrome. Among the proposed mechanisms for benefit is the promotion of nerve regeneration via enhancing Erk 1/2 and Akt activities.
B12 Administration
The Irish Journal of Medical Science published a systematic review and network meta-analysis evaluating the efficacy of each form of vitamin B12 administration, i.e., oral, intramuscular (IM) injection, or sublingual, for instances of B12 deficiency. In 2018, a Cochrane review comparing oral to IM included an analysis of 3 randomized trials with a total of 153 participants, found that while oral supplementation had similar effects on normalizing serum levels, the evidence was very low quality, with poor randomization, blinding, small samples, etc.; thus there remains doubt concerning the efficacy of oral (and sublingual) supplementation, particularly with documented B12 deficiency which may indicate malabsorption. The Cochrane review noted that the oral dose is important; an oral dose of 2 mg per day (total dose over time of 240 mg) resulted in significantly higher serum levels (680 pg/mL higher) compared to an IM dose of 1 mg per day (total dose 9 mg).
While most B12 absorption occurs via an active process (B12 is bound by intrinsic factor produced from parietal cells, and absorbed in the terminal ileum), approximately 1% of an oral dose is absorbed by passive diffusion. This potentially allows for adequate treatment of B12 deficiency with large enough oral doses, even in the absence of intrinsic factors (such as with pernicious anemia), but studies are few and have limited participants.
This recent systematic review included 13 studies, 8 of which were randomized trials, with over 4200 participants with vitamin B12 deficiency. Each type of administration was found to increase serum levels, with the largest effect attributed to IM, followed by sublingual, then oral. However, no clinically meaningful difference was observed between the three methods of administration. Similarly, no meaningful difference was observed on parameters related to B12 deficiency, such as hemoglobin, MCV, homocysteine, etc. Thus, the choice of method may depend on other factors, such as the ability to eat or drink, the presence of severe nausea/vomiting, etc. The authors of this review suggest that the sublingual method may be generally preferable, as it has more advantages (such as rapid systemic impact) and fewer disadvantages.
One of the largest studies comparing sublingual vs. IM administration was a retrospective analysis that included over 4000 participants, with approximately 80% receiving sublingual B12 vs. 20% receiving IM. This analysis reported significantly higher serum B12 levels with sublingual therapy, 252 vs. 218 ng/L. One of the largest trials comparing oral supplementation to IM was a randomized clinical non-inferiority trial with a follow-up of 1 year conducted among 229 patients over 65 years old. It compared an IM dose of 1 mg B12 every other day for 2 weeks, 1 mg/week for weeks 3–8, and 1 mg/month in weeks 9–52 to an oral dose of 1 mg/day in weeks 1–8 and 1 mg/week during weeks 9–52. Very similar efficacy was reported, with a low probability of differences between the two in terms of achieving serum B12 sufficiency, and over 80% of participants reported a preference for oral B12. However, the authors did note that one predictor of success at 1 year was having reached a serum B12 level of ≥281 pg/mL by week 8; these participants were 8-fold more likely to achieve sufficiency at 1 year. Among participants not meeting the above threshold by week 8, the authors propose that a higher maintenance dose could be used, such as 2 mg/week or more.
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